Impact and cost-effectiveness of non-governmental organizations on the HIV epidemic in Ukraine among men who have sex with men

Objective Non-governmental organisations (NGOs) in Ukraine have provided HIV testing, treatment, and condom distribution for men who have sex with men (MSM). HIV prevalence among MSM in Ukraine is 5.6%. We estimated the impact and cost-effectiveness of MSM-targeted NGO activities in Ukraine. Design A mathematical model of HIV transmission among MSM was calibrated to data from Ukraine (2011-2018). Methods The model, designed before the 2022 Russian invasion of Ukraine, evaluated the impact of 2018 status quo (SQ) coverage levels of 28% of MSM being NGO clients over 2016-2020 and 2021-2030 compared to no NGO activities over these time periods. Impact was measured in HIV incidence and infections averted. We compared the costs and disability adjusted life years [DALYs] for the SQ and a counterfactual scenario (no NGOs 2016-2020, but with NGOs thereafter) until 2030 to estimate the mean incremental cost-effectiveness ratio (ICER, cost per DALY averted). Results Without NGO activity over 2016-2020, the HIV incidence in 2021 would have been 44% (95%CrI: 36%-59%) higher than with SQ levels of NGO activity, with 25% (21-30%) more incident infections occurring over 2016-2020. Continuing with SQ NGO coverage levels will decrease HIV incidence by 41% over 2021-2030, whereas it will increase by 79% (60-120%) with no NGOs over this period and 37% (30-51%) more HIV infections will occur. Compared to if NGO activities had ceased over 2016-2020 (but continued thereafter), the SQ scenario averts 14,918 DALYs over 2016-2030 with a mean ICER of US$600.15 per DALY averted. Conclusions MSM-targeted NGOs in Ukraine have prevented considerable HIV infections and are highly cost-effective compared with a willingness-to-pay threshold of 50% of Ukraine’s 2018 GDP (US$1,548).


Introduction
The Eastern Europe and Central Asia region has a fast growing HIV epidemic (1), with Ukraine having the second largest HIV burden (2). Men who have sex with men (MSM) have a high prevalence of HIV in Ukraine (5.6% in 2018(3)), however, it is difficult to estimate the overall number with HIV due to stigmatisation of MSM (4).
Most funding for HIV treatment and prevention services in Ukraine, including among MSM, goes to non-governmental organisations (NGOs) (5). NGOs targeting MSM provide HIV testing and counselling services, distribute condoms, and link HIV-diagnosed people to antiretroviral therapy (ART) at government AIDS centres. Condom use can reduce the transmission of HIV among MSM (6,7), while ART renders HIV untransmissible if people's viral loads are undetectable (8,9). In our previous epidemiological analyses utilising four national integrated bio-behavioural surveys (IBBS) among MSM in Ukraine, we found that being in contact with MSM-targeted NGOs was associated with increased condom use and HIV testing, and greater likelihood of being on ART (10).
To help policymakers allocate their limited resources, information is needed on the benefits and costs of different health interventions. This has become particularly important in middle-income countries such as Ukraine because funding for NGO activities is transitioning from international funding agencies to governments (11). Although the recent invasion by Russia has radically changed Ukraine's priorities, it is still important to show the benefit of these interventions to emphasise that services should still provide for the needs of this sub-population, and to show the potential implications of not doing so. To this end, we utilise findings from our previous epidemiological analyses(10) within a mathematical modelling framework to evaluate the impact and cost-effectiveness of MSM-targeted NGO activities on the Ukrainian HIV epidemic among MSM.

Model summary
We developed a dynamic, deterministic model of HIV transmission among MSM (schematic in supplementary figure 1), stratified by age (18-39 and ≥40 years), low and high sexual risk behaviour (<10 and ≥10 anal sex contacts per month), NGO status, and HIV disease progression, diagnosis, and treatment. Individuals enter the model at age 18 as HIV-negative (susceptible) and not accessing NGOs, with a constant proportion being high-risk and the remainder low-risk. Individuals exit due to age-related or HIV-related deaths, with only the former being replaced with new entrants.
Transitions occur between the low-and high-risk groups at rates that differ for ages  and ≥40 years but balance the flows between these groups. MSM become clients of NGOs at time-varying rates from 2003 and cease contact with NGOs at a constant rate. HIV-positive MSM become NGO clients at a higher rate due to NGO efforts to link HIV-positive MSM to care; our previous analyses show a higher proportion of NGO clients are HIV-positive than for non-NGO clients (10).

HIV transmission and progression
We assume all HIV transmission is within the MSM population as few MSM (2%; IBBS) have ever injected drugs and most HIV-infected women are female sex workers (12,13), which few MSM have sex with (last 6 months: 2%; IBBS). Uninfected MSM become infected at a rate proportional to the prevalence of HIV among MSM and the frequency of sex among low/high-risk MSM. HIV transmission is reduced through condom use, with consistency of use varying by risk level and NGO status. Differences in condom use across partnerships are averaged.
Following HIV infection, individuals progress through acute, latent, pre-AIDS, and AIDS stages of HIV disease. Transmissibility is heightened during acute infection and pre-AIDS HIV disease (14), whereas AIDS patients do not engage in sexual activity unless on ART. Individuals with AIDS die from HIV-related disease. Individuals with chronic HIV infection, pre-AIDS, or AIDS can be diagnosed and enrolled onto ART. Individuals can be lost-to-care from ART and can then re-initiate ART at the same rate as ART-naïve MSM. Individuals on ART are less infectious, and experience reduced HIV progression and mortality than individuals not on ART.
Pre-exposure prophylaxis (PrEP) is not readily available in Ukraine (15). A full model description is in the supplement.
Age-related mortality data comes from UN databases (19) and we use existing population size estimates for MSM in Ukraine (~181,000(20)).
The model is seeded so that the age distribution of MSM in 1990 matches Ukraine's male population, with MSM then entering and aging through the model. Although the HIV epidemic probably started later in Ukraine than Western Europe (21), there is considerable uncertainty around the initial epidemic, so we varied the number of seeded HIV-positive MSM in 1990 (0-2.8% prevalence).
In our previous analyses of the MSM IBBS data, being an NGO client was associated with(10): , which are successively perturbed to improve their goodness of fit, with this ceasing when there is no improvement between successive iterations. This produced 500 baseline model fits, which were used for all model analyses to produce a median estimate and 95% credibility intervals around that estimate, defined as the 2.5 th -97.5 th percentile range.

Modelled impact analyses
We modelled the impact of existing coverage levels of NGOs (status quo) over 2016-2020, and if they were continued over 2021-2030, both compared to counterfactual scenarios where there was no effect of NGOs on condom use, HIV testing and initiating ART over these specific time periods, equivalent to NGOs ceasing activities and their effects stopping over these time periods. Although the recent invasion by Russia will have changed the status quo situation, it is too early to understand to what degree, with the counterfactual situation now also being relevant to show what could occur if services are disrupted compared to them being maintained. For the 2021-2030 scenario, we also varied the counterfactual to estimate the impact of each beneficial effect of the NGOs. We also estimated the impact over 2021-2030 of increasing the coverage of NGOs from 28% to 60% of MSM by 2025. Impact was estimated in terms of the number and percentage of HIV infections averted, percentage reduction in HIV incidence and HIV prevalence, and number and percentage of HIV deaths averted.
To investigate our assumptions about the effectiveness of NGOs, we also performed a sensitivity analysis in where we assumed not all the differences in condom use, HIV testing and ART coverage between NGO and non-NGO clients were due to NGO activities. For these, the counterfactual scenario incorporated different percentages of the difference in condom use, HIV testing, and linkage to HIV care between NGO and non-NGO clients. The status quo scenario was then compared to these scenarios. This can be interpreted as different percentages of the effects we are currently prescribing to NGOs being due to other causes.

Cost-effectiveness analysis
Unit cost estimates for ART and NGO services for MSM (HIV counselling and testing, condom distribution, post-diagnosis HIV case management) came from published reports (27)(28)(29) and unpublished APH operational budget data for Ukraine (collected and provided by APH co-authors). Further details on the cost and health utility assumptions are given in the supplementary materials.
Due to the ongoing nature of NGO activities, we estimated the cost-effectiveness of current NGO activities by comparing the status quo scenario over 2016-2030 with a counterfactual scenario where NGO activities are stopped for 5 years (costs and effects of NGOs are removed) from 2016 and then restarted in 2021 until 2030. This allows us to capture some of the longer-term benefits of the NGO activities that occurred over 2016-2020 (30,31). This was done across all 500 baseline model fits (probabilistic sensitivity analysis or PSA) to produce a joint distribution for the incremental costs and DALYs between the intervention and counterfactual scenario, with all future costs and outcomes discounted at 3% per year. The mean incremental cost-effectiveness ratio (ICER) was calculated across the PSA outputs in terms of incremental cost per DALY averted. This was compared against a willingness-topay threshold of 50% of Ukraine's per capita GDP in 2018 (US$3,096*0.5= US$1,548), the lowest estimated willingness-to-pay threshold for Ukraine based on health opportunity costs (33). Cost-effectiveness acceptability curves were plotted to determine the proportion of simulations that are cost-effective as a function of these willingness-to-pay thresholds.  Figure 1 shows the modelled scale-up in NGO activities over time, fitted to APH data, with peak coverage reached around 2018, dropping in 2020 due to COVID-19. Supplementary figures 2 and 3 show that the model generally fitted the IBBS HIV prevalence and ART coverage data well. In addition, the model also agrees well with HIV incidence data not used in the model calibration, as shown in Figure 2.

Status quo model projections
With existing levels of NGO activity (supplementary If NGO activities were to cease over 2021-2030, then the number of incident HIV infections over this period would increase by 37% (95%CrI: 30%-51%) compared to the status quo scenario, HIV incidence in 2030 would be 79% (95%CrI: 60%-120%) higher, and 15% (95%CrI: 12%-20%) more deaths would occur ( figure 3). Importantly, the increase in HIV incidence would occur quickly (Figure 3) highlighting that disruptions in NGO activities could quickly reverse decreasing trends in HIV incidence.

Comparison with literature
To our knowledge, this is the first study to examine the impact and cost-effectiveness of MSM-targeted NGOs in Ukraine. Wirtz et al previously modelled the impact of HIV prevention and treatment interventions among MSM in various low-and middle-income countries (LMIC), including Ukraine, and found that little impact on HIV incidence would be achieved unless ART was expanded (34). Unfortunately, little data for these analyses came from Ukraine and they did not calculate the cost-effectiveness of the interventions.
There has been limited research on Ukraine's HIV epidemic among MSM. Our previous study used in this analysis found that NGOs were associated with beneficial outcomes among MSM(10), agreeing with other research (35). An MSM modelling study in Poland found that immediate initiation of HIV treatment was cost-saving from the public perspective (36). This was also a benefit of NGOs in Ukraine, enabling quicker diagnosis and linkage to HIV treatment. A review of spending on HIV in Eastern Europe and Asia found that programmes targeting MSM were moderately cost-effective, although there were few studies (37). Further afield, a study in Southern India showed that a large-scale intervention programme for HIV among MSM increased condom use, averted many HIV infections and was cost-effective (38 (58,59) or antenatal testing with a dual rapid test for HIV and syphilis (varying from cost-saving to $205 per DALY averted) (60).

Strengths and limitations
The strength of our modelling includes using four rounds of national IBBS data to parameterise and calibrate the model within a Bayesian framework. Another strength is its novelty, with there being few evaluations of MSM-targeted interventions for Eastern Europe (61). Limitations include uncertainty around the MSM population size in Ukraine due to stigmatized around this population(4). Although we used the current best estimate for this parameter, there were limitations to the methods employed(20). There was uncertainty in other model parameters, which was incorporated into the model calibration, and the results were robust despite this. There was limited information on older MSM (aged ≥40) because they were not sampled well in the IBBS surveys.
The IBBS surveys are also limited because they are observational, and, so, could only be used to look at associations rather than causality in the epidemiological analyses that fed into this modelling. It is possible that some of our modelled intervention effects may result from more health-conscious people attending NGOs or from risk-behaviours differing between HIV-negative and HIV-positive MSM (HIV-positive MSM attended NGOs more than HIV-negative MSM), resulting in our projections possibly being overestimates. To counter this, we showed using stratified analyses that the beneficial associations of being an NGO client remained for both HIV-negative and HIV-positive MSM (supplementary page 21). Also, model sensitivity analyses found that NGOs still had considerable impact and were cost-effective even when we assumed some of the beneficial effects attributed to NGOs were due to other reasons. Conversely, we may be underestimating the impact of NGOs because our modelling only considers the effect of NGOs on their clients, rather than anyone reached by outreach services. Additionally, we did not incorporate the onward benefits of MSM interventions to their female partners. The perspective of this analysis is in terms of the payer (the Ukrainian government), however, the scope is only for ART, OST, and NGO costs, and do not include costs regarding health promotion or other healthcare costs related to PLHIV over time, as we did not have data to estimate them. In the 2018 IBBS report, viral suppression among HIV-positive MSM in Ukraine was 76% using a threshold of 1000 copies/mL(3), however, testing was performed upon a selected subgroup that self-reported being on ART, so we did not incorporate this into our analysis. Lastly, we incorporated the effect of COVID-19 on NGO interventions in 2020, suggesting a 10% decrease in MSM contacts.

Conclusion
Our analyses suggest that NGOs targeting MSM in Ukraine are highly cost-effective and have been preventing considerable HIV infections and deaths. This beneficial impact has been achieved through condom distribution, while quickly diagnosing HIV-positive MSM and linking them to ART (9). Unfortunately, the Russian invasion is affecting the country's response to the HIV epidemic (62). Although evidence suggests NGOs are still providing HIV services in many areas, HIV testing is reduced, and some regions are much worse affected. In the current situation, our findings are important for emphasising Europe PMC Funders Author Manuscripts why these services should continue in Ukraine, while for other settings they are useful for guiding policymakers on how to optimally allocate their resources to achieve greatest health benefits. These analyses were undertaken at a time when Ukraine was undergoing a decrease in monetary support from the Global Fund (11) with funding transitioning to the Ukraine government. Even before Russia's 2022 invasion, additional stresses were being placed on Ukraine's economy by the war with Russia from 2014 (63,64) and the COVID-19 pandemic (65). Our analyses show that MSM HIV programming should continue, because otherwise the HIV epidemic among MSM will increase considerably. As stated by others (27), it is crucial that policymakers in Ukraine and other low-and middle-income countries are aware of the large, preventive effect that NGOs can and are having on HIVtransmission.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Conflicts of interest and sources of funding
NS, TS, and OV work for the Alliance for Public Health (APH), Ukraine, which is a non-governmental organisation. The Global Fund to fight AIDS, tuberculosis, and malaria (GF) or other international funders had no role in these analyses or in decisions to publish. APH is one of the largest recipients in Ukraine of funding from the GF, and the salary of TS is funded through grants from the US Centers for Disease control, with OV's salary partially funded from a GF grant. JS reports non-financial support from Gilead Sciences, outside the submitted work. JGW and PV report research grants from Gilead unrelated to this work. The corresponding author had the final decision to publish and APH did not influence how the analyses were performed.   NGO: Non-governmental organisation.  * Sensitivity analysis where we assumed not all the differences in condom use, HIV testing and ART coverage between NGO and non-NGO clients were due to NGO activities. For these, the counterfactual scenario incorporated different percentages of the difference in condom use, HIV testing, and linkage to HIV care between NGO and non-NGO clients. The status quo scenario was then compared to these scenarios. This can be interpreted as different percentages of the effects we are currently prescribing to NGOs being due to other causes.